EP3400932B1 - Mischung von stabilisiertem biologisch verfügbarem curcumin für orodispergierbare formulierungen, formulierungen von biologisch verfügbarem curcumin und orodispergierbare tablette mit biologisch verfügbarem curcumin und verwendung davon - Google Patents

Mischung von stabilisiertem biologisch verfügbarem curcumin für orodispergierbare formulierungen, formulierungen von biologisch verfügbarem curcumin und orodispergierbare tablette mit biologisch verfügbarem curcumin und verwendung davon Download PDF

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EP3400932B1
EP3400932B1 EP18170818.1A EP18170818A EP3400932B1 EP 3400932 B1 EP3400932 B1 EP 3400932B1 EP 18170818 A EP18170818 A EP 18170818A EP 3400932 B1 EP3400932 B1 EP 3400932B1
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curcumin
orodispersible
biologically available
weight
tablet
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French (fr)
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EP3400932A1 (de
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Jan Stonis
Ivan Mikes
Andrea Dolezalova
Jarmila Kralova
Milan Jakubek
Pavel Martasek
Vladimir Kral
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Mcepharma S R O
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Mcepharma S R O
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • Orodispersible tablets containing highly biologically available curcumin as food additive are provided.
  • Curcumin is a yellow dye isolated of curcuma alias Indian saffron, an extract coming from a rhizome of turmeric (Curcuma longa). Curcumin is the most biologically active component of curcuma and it has attracted a great attention because of many performed and finished scientific studies which indicate that it can have many healthy benefits. Curcumin has been a subject of intensive research for example due to its antitumour effects, for its prophylactic effects against diseases of affluence, for its prophylactic effects against development of both Alzheimer's and Parkinson's diseases, and last but not least for its antiinflammatory and analgesic effects.
  • the extract of curcuma is the extract of rhizome of plant Curcuma longa. This extract is expected to have many beneficial healthy effects on the cardiovascular system, immune system, performance of liver, digestion, activity of the nerve system, function of the respiratory system, condition of skin and course of inflammatory reactions. Curcumin is the most biologically active component of this extract.
  • Curcuma extract is commonly available in the form of tablets, hard capsules, soft gelatine capsules and as emulsion.
  • orodispersible tablets and minitablets are known. These tablets are suitable to all the patients who have problems with tablets swallowing or who do not like it, both children and seniors. Orodispersible formulations represent an alternative for these customers and they improve the application comfort in using food additives.
  • the orodispersible drug forms are also advantageous for patients suffering from nausea, vomiting and diarrhoea. As the active substance is applied using the orodispersible drug form, there is quicker absorption of the medicinal component which runs less through mouth mucosa but most active substance is absorbed in the pre-gastric part of the digestive tract, and this causes marked decrease of the first-pass effect of liver metabolism, and this results in marked rise of efficiency of the administered active substance and of its dose.
  • the drug form improves the clinical effect of some active substances through increasing their bioavailability and decreasing occurrence of side effects due to by-passing first-pass of the liver metabolism effect.
  • Formulating orodispersible preparations is demanding for several various reasons. Above all, this drug form must break down very quickly in the oral cavity. Moreover, too early release of an active substance in the mouth can result in problems with their application because of unpleasant taste of the active substance.
  • the selected drug form should be adequately porous, so that it would break down quickly, but on the other hand it must bear mechanic load during transportation, storing and application. It is familiar that porous structures are very sensitive on air moisture and thus, problems concerning stability in long-time storing can develop. And finally, an orodispersible drug form with required organoleptic and pharmacokinetic properties must also be produced in commercially meaningful and applicable quantities.
  • spray drying involves spraying of solution of active substance, of additional substances or of a mixture of both in a chamber where high temperature is maintained. This approach is not suitable for processing of thermolabile active substances or additional substances. Moreover, spray drying is very expensive and for this process it is characterised by high loss of the final product.
  • Lyophilization is a technique to remove moisture or solvent from solution using decreased temperature and decreased pressure. Unfortunately, it losses efficiency under large production scale and it is also limited by high price of the equipment, it is timely demanding and process conditions are difficult to maintain.
  • An example can be Zydis ® Technique. Tablets prepared using this technique are very brittle and they must be transported, stored and applied in a special case - adapted form of classical blister. These formulations are treated in US patents 4 642 903 , 5 188 825 , 5 631 023 , 5 827 541 and 5 976 577 .
  • wet granulation is an agglomeration technique with which granulated powder of high strength can be acquired, it breaks down slowly and thus is is not suitable for orodispersible drug forms.
  • Use of solvents and added steps for drying which this technique required, can moreover result in changes of polymorphic and pseudopolymorphic form of an active and/or additional substance and its degradation.
  • curcumin One of the issues related to curcumin is its biological availability. Even under high doses of native curcumin, only very small quantity reaches circulation after oral administration because of its quick metabolic conversion both in liver and in intestinal wall. A human body very poorly absorbs curcumin administered separately and the body can process only a small share of the administered dose efficiently. Capsules containing soya lecithin (Meriva) are produced to increase efficiency and bioavailability, use of nanotechniques (Theracurcumin) and dilution in water using polyvinylpyrrolidone is investigated. This method has claimed up to 46 times increased absorption when compared with the standard mixture of curcumin. Common application of curcumin together with piperine, an extract of black pepper, is a very efficient option.
  • Curcumin C3 complex by Sabinsa, described in the patent document WO97/03674 , has been used for comparison with marking "B Product”.
  • This product consists of extract of curcuma with 95% by weight of curcumin, demethoxycurcumin and bisdementhoxycurcumin of 300 mg. The extract was mixed together with piperine 2 mg, celulose and magnesium stearate and they together are sealed in gelatine capsules.
  • Liftea curcumin has been used for comparison with marking "A Product”.
  • Liftea curcumin is a preparation of extract of curcuma (95% of curcuminoids by weight) of 157 mg with 300 mg of inuline in a gelatine capsule containing magnesium stearate (antisintering agent).
  • extract of curcuma 95% of curcuminoids by weight
  • inuline 300 mg
  • inuline 300 mg
  • magnesium stearate antisintering agent
  • a system for orodispersible formulations containing biologically available curcumim has been developed that operated at 200 times higher biological availability and 220 times higher solubility of curcumim against native curcumim involved in common food additives.
  • a mixture of stabilised biologically available curcumin for orodispersible formulations contains particles of extract of rhizome of plant Curcuma longa containing 95% by weight of curcumin ground in the dry way in mixture with mannitol in the 1 : 1 weight ratio or any excess of mannitol to size of particles 100 to 250 nm, at least.
  • an orodispersible tablet with biologically available curcumin has been produced increasing biological availability of mixture of stabilised biologically available curcumin by 30% that contains formulation of biologically available curcumin in orodispersible carrier that contains 20 to 80% by weight of tapioca starch, 10 to 30 % by weight of pulverized bamboo fibre and 1 to 20% by weight of acid hydrolysed dextrine.
  • This system for orodispersible formulations containing biologically available curcumin increases bioavailability of curcumin little by little, and it has been tested against the whole orodispersible tablet which shows up to 100% bioavailability and 92% bioavailability formulations of biologically available curcumin and the 72% bioavailability of mixture of stabilised biologically available curcumin has been related to it.
  • curcumin extract through oral mucosa, it has 220 times better solubility and 200 times better absorption ability and, above all, proven biological absorption ability for human cells.
  • Orodispersible tablets (ODT) and minitablets (ODMT) allow absorbance of curcumin directly through oral mucosa and pre-gastric parts of the digestive tract, without necessary pass through the digestive tract.
  • Tablets and minitablets are suitable for vegans and vegetarians and even for persons suffering from food allergy, they contain neither lactose nor gluten.
  • direct compression of tablets and minitablets follows and thus no further granulation, other production step or additive are necessary. It is not necessary to wash down tablets or minitablets, it is enough to solve them in mouth.
  • the process of producing tablets and minitablets is not time-consuming, it represents high yields of the product, and there is no change in the form of the active substance or its reduction in production.
  • the mixture of stabilised biologically available curcumin contains particles of curcumin extract in size 110 - 180 nm.
  • Formulation of biologically available curcumin increases biological availability of mixture of stabilised biologically available curcumin for orodispersible formulations by 20% and it contains mixture of stabilised biologically available curcumin in lipide in weight ratio 0.35 to 1.5 :1 of lipide against curcumin under presence piperine in weight ratio 0.0025 to 0.1 :1 piperine against curcumin, and it is advantageous to use lecithin as lipide.
  • An orodispersible tablet with biologically available curcumin increases biological availability of mixture of stabilised biologically available curcumin by 30% and it contains formulation of biologically available curcumin in orodispersible carrier which contains 20 to 80 % by weight of tapioca starch, 10 to 30% by weight of pulverized bamboo fibre and 1 to 20% by weight of acid hydrolysed dextrin.
  • Curcumin extract is processed using jet or pin grinding with very uniform resulting distribution of particles, medium size of particles is 170 nm and 115 nm for jet and pin grinding, respectively.
  • the ideal stabiliser for grinding of curcumin particles proved to be mannitol.
  • Mixture of stabilised biologically available curcumin is prepared by common dry grinding of curcumin extract with manitol, namely in precise ratio at least 1:1 or with manitol excess. This ratio provides for stability of ground nano-curcumin when reverse aggregation of curcumin nanoparticles to larger units does not occur, which would result in decreasing bioavailability. It is advantageous to have the weight ratio mannitol:curcumin je 2:1, and also ratio 1 to 3:1 is functional. Further increase of mannitol content in the mixture has no effect on size and stabilisation of curcumin nanoparticles and it only dilutes the active substance content.
  • particle size is in the interval from 130 to 250 nm.
  • Curcumin is ground with stabiliser, it is advantageous with mannitol, it is advantageous in ratio 2:1 (mannitol:curcumin) in a dry way in a jet grinder.
  • Feed pressure is 30 to 70 PSI (206.843 kPa to 482.633 kPa), grinding pressure 30 to 70 PSI (206.843 kPa to 482.633 kPa) and the ground process is repeated twice. This the required medium size of particles and narrow distribution particles are achieved which provide for high bioavailability of curcumin.
  • particle size is in the interval from 100 to 170 nm.
  • Curcumin is ground with stabiliser, it is advantageous with mannitol, it is advantageous in the ratio 2:1 against curcumin in a dry way in a pin mill.
  • rotors OR PV rotors OR PV with round tools of the type or rotors BR PV or rotors BR PV with controlled flow of material (or with slowing flow of material and its compaction in intermediate spaces which are combined with spreaders labelled 11 and 12. Feeding of material in the machine is manual or vibration. This way decreased size of particles and narrow distribution particles are achieved which provide for high bioavailability of curcumin.
  • Formulation of biologically available curcumin is added to additive, orodispersible carrier which forms a resulting form of a tablet or a minitablet which is easily soluble in the mouth and it is mostly produced of natural raw materials.
  • Formulation of biologically available curcumin contains piperin and lipid, it is advantageous if lecithin. Piperin blocks function of digestive enzymes, processing curcumin, and it increases its bioavailability indirectly. Lipid changes surface tension of cell membranes and it has a positive effect on bioavailability of curcumin and its penetration in cells. This way it facilitates absorption of curcumin in the tissue.
  • a mixture of ground curcumin, mannitol, piperine and lecithine, thus formulation of biologically available curcumin is mixed s tablet substance/orodispersible carrier which is composed of several components and which is prepared using the fluid granulation process.
  • This method provides for generation of porous structure of granulated powder which breaks down quickly but, on the other hand, it is resilient enough to withstand transport of tablets.
  • filling agents (tapioca starch, bamboo fibre) are suspended in flow of heated air.
  • the solution of a binding agent containing dextrine and Stevio-Rebauosid A, advantageous if isomalt or sorbitol, is applied into this way formed fluid bed.
  • the purpose of the binding agent is to create physical link among the free particles of powder (starch, pulverized bamboo fibre) and finally to form a granulate.
  • the granulate is dried while suspended and then it is advantageous to add sweetening agents (erythritol, sorbitol or xylitol) which keep pleasant feeling after being dissolved in the mouth and also it is advantageous to add pre-gelatinized starch, silicon dioxide and glyceryl dibehenate and then the mixture is mixed properly.
  • Is is advantageous to use aroma or flavour, for example orange, peppermint, citrone, strawberry, banana, raspberry, sour cherry, cherry or other, for better feeling in the mouth after the tablet is administered.
  • aroma or flavour for example orange, peppermint, citrone, strawberry, banana, raspberry, sour cherry, cherry or other, for better feeling in the mouth after the tablet is administered.
  • Bioavailability of curcumin in an orodispersible tablet has been compared against commercial preparation labelled as products A and B. Bioavailability and solubility have been tested through measurement of fluorescence of a tablet diluted in solution and after absorption in tumour cells - in vitro tests. Examples document that penetration of ground curcumin in cells has really occurred, namely up to 13times more efficiently against commercial preparations where relative intensity of green fluorescence of curcumin in cell nucleus for products A and B is 2.33 and 1.93, respectively, while relative intensity of green fluorescence of curcumin in cell nucleus of biologically available curcumin according to the invention is 22.74.
  • bioavailability of products A and B is only 10% and 8%, respectively, against bioavailable curcumin in an orodispersible tablet according to the invention.
  • the tests on solubility of biologically available curcumin have been carried out in PBS buffer and they have shown that the complete dissolution of tablets can occur within 30 seconds. Solubility has been measured through intensity of fluorescence and it has been for biologically available curcumin 220times higher than for the A product.
  • the optimum composition has shown to be tapioca starch (20 to 80 % by weight), pulverized bamboo fibre (10 to 30 % by weight ), erythritol (10 to 50 % by weight), pre-gelatinised starch (0.01 to 10 % by weight), acid hydrolysed dextrine (1 to 20 % by weight), silicon dioxide (0.5 to 4 % by weight) and glyceryl dibehenate (0.4 to 4 % by weight).
  • slippy substances can function instead silicon dioxide and glyceryl dibehenate, e.g. magnesium stearate, aluminium stearate, sodium lauryl sulphate, talc, polyethylene glycol, stearic acid, boric acid, namely in concentration 1 to 8 % by weight, best if 1 to 5 % by weight.
  • Aroma can be used in concentration 0.01 to 10 % by weight.
  • Tablets weight 150 to 300 mg and their diameter is 7 to 12 mm.
  • Minitablets weight 35 to 70 mg and their diameter is 4 to 6 mm.
  • Minitablets have strength 5 to 100 N, best if 20 to 50 N and their abrasion is less than 1%.
  • ground curcumin extract a vast series of specimens of different size of particles ground curcumin extract has been tested, and the best solubility and bioavailability has been found in ground curcumin with the size 115 to 180 nm.
  • Curcuma of rhizome of plant Curcuma longa L. has been used as parent raw material for extraction.
  • the extract has contained 97.03 % by weight of curcumin and ash content has been 0.05 % by weight.
  • the full certificate for analysis of the used extract is presented in Fig. 1 .
  • 25 g of curcumin extract has been ground in a dry way in a laboratory jet mill together with mannitol in ratio 2:1 (mannitol against curcumin).
  • the input feed pressure has been 70 PSI (344.738 kPa) and grinding pressure has been 50 PSI (482.633 kPa).
  • the grinding process has run once for 96 minutes at 25°C.
  • the resulting medium size of particles of ground curcumin has been measured using dynamic light dispersion and it has ranged around 335.735 nm.
  • the detailed results of the ground extract analysis are in Fig. 2 .
  • This medium size of particles has been determined as unsuitable for use as a highly absorbable active substance.
  • Curcuma with botanic name Curcuma longa L. has been used as the parent raw material for extraction.
  • the extract has contained 97.03 % by weight of curcumin and ash content has been 0.05 % by weight.
  • the full certificate for analysis of the used extract is presented in Fig. 1 .
  • 250 g of curcumin extract has been ground in a dry way in a laboratory jet mill together with 500 g of mannitol, i.e. in ratio 1:2.
  • the input feed pressure has been 50 PSI (482.633 kPa) and grinding pressure has been 50 PSI (482.633 kPa).
  • the grinding process has run twice subsequently for 96 minutes at 25°C.
  • the resulting medium size of particles of curcumin has been measured using dynamic light dispersion and it has been determined as 171.17 nm which has been the smallest achieved medium size of particles; distribution of particles has been (134.16 to 246.98 nm).
  • the detailed results of the ground extract analysis are in Fig. 3 .
  • This medium size of particles has been determined as suitable for use as a highly absorbable active substance.
  • Curcuma with botanic name Curcuma longa L. has been used as the parent raw material for extraction.
  • the extract has contained 97.03 % by weight of curcumin and ash content has been 0.05 % by weight.
  • the full certificate for analysis of the used extract is presented in Fig. 1 .
  • 300 g of curcumin extract has been ground in a dry way in a laboratory pin mill together with 600 g of mannitol, i.e. in ratio 1:2.
  • the OR PV rotor with round tools has been used as the rotor, combined with spreader 11.
  • the resulting medium size of particles of curcumin has been measured using dynamic light dispersion and it has been determined as 115.5 nm which has been the smallest achieved medium size of particles; distribution of particles has been (100.02 - 171.25 nm).
  • the detailed results of the ground extract analysis are presented in Fig. 4 .
  • This medium size of particles has been determined as suitable for use as a highly absorbable active substance.
  • Tablet substance in the function of a carrier matrix tablet and a minitablet, without active substances, have been prepared in a fluid granulation process.
  • 713.294 g of tapioca starch and 124.802 g of pulverized bamboo fibre has been suspended in flow of air heated to 80 to 90° C. Little by little a solution has been applied in the created fluid bed.
  • the solution has been generated by dilution of 14.799 g of LyckebyPlus 1200H and 0.636 g of Stevia-Rebausiode A in hot water. After application of the solution, the generated granulate has been dried suspended, till it has contained 4 to 8% by weight of residual moisture.
  • Tablet substance in the function of a carrier matrix tablet and a minitablet, without active substances, have been prepared in a fluid granulation process.
  • 692.562 g of tapioca starch and 221.525 g of pulverized bamboo fibre has been suspended in flow of heated air. Little by little a solution has been applied in the created fluid bed.
  • the solution has been generated by dilution 15.845 g of Lyckeby plus 1200H and 0.883 g of Stevio-rebauoside A in hot water. After application of the solution, the generated granulate has been dried suspended, till it has contained 4-8% by weight of residual moisture.
  • Tablet substance in the function of a carrier matrix tablet and a minitablet, without active substances, have been prepared in a fluid granulation process.
  • 559.512 g of tapioca starch and 215.525 g of pulverized bamboo fibre has been suspended in flow of heated air. Little by little a solution has been applied in the created fluid bed.
  • the solution has been generated by dilution of 16.799 g of isomalt and 0.883 g of Stevio-rebauoside A in hot water. After application of the solution, the generated granulate has been dried suspended, till it has contained 4 to 8 % by weight of residual moisture.
  • Tablet substance in the function of a carrier matrix tablet and a minitablet, without active substances, have been prepared in a fluid granulation process.
  • 706.512 g of tapioca starch and 240.802 g of pulverized bamboo fibre has been suspended in flow of heated air. Little by little a solution has been applied in the created fluid bed.
  • the solution has been generated by dilution of 13.845 g of sorbitol (NeoSorb) and 0.883 g of Stevio-rebauoside A in hot water. After application of the solution, the generated granulate has been dried suspended, till it has contained 4 to 8% by weight of residual moisture.
  • Example 4 A To 400 g of tablet substance prepared according to Example 4 A, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 2, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of lecithin, 0.2 g of piperine and 6.67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • 60 g of mixture of stabilised nanocurcumin prepared according to Example 2 i.e. 20 g of ground curcumin and 40 g of mannitol
  • 30 g of lecithin 30 g of lecithin
  • 0.2 g of piperine 0.2 g of piperine
  • 6.67 g of orange aroma All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • Example 3 To 400 g of tablet substance prepared according to Example 3, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of lecithin, 0.2 g of piperine and 6.67 g of peppermint aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B i.e. 20 g of ground curcumin and 40 g of mannitol
  • 30 g of lecithin 30 g of lecithin
  • 0.2 g of piperine 0.2 g of piperine
  • 6.67 g of peppermint aroma All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • Example 4 B To 223 g of tablet substance prepared according to Example 4 B, the substances as follows have been added: 160 g of mixture of stabilised nanocurcumin prepared according to Example 1B with ratio mannitol:curcumin 1:1, i.e. 80 g of ground curcumin and 80 g of mannitol, 30 g of lecithin, 0.2 g of piperine and 6.67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • Example 3 To 223 g of tablet substance prepared according to Example 3, the substances as follows have been added: 160 g of mixture of stabilised nanocurcumin prepared according to Example 2 with ratio mannitol:curcumin 1:1, i.e. 80 g of ground curcumin and 80 g of mannitol, 30 g of lecithin, 0.2 g of piperine and 6.67 g of peppermint aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • Example 4C To 400 g of tablet substance prepared according to Example 4C, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 2, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of sunflower lecithin and 0.17 g of piperine. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • Example 3 To 409 g of tablet substance prepared according to Example 3, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 1A, i.e. 20 g of ground curcumin and 40 g of mannitol, 20 g of sunflower lecithin and 0.17 g of piperine. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 50 mg.
  • Example 3 To 1903 g of tablet substance prepared according to Example 3, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 2, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of lecithin, 0.2 g of piperine and 6.67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 150 mg.
  • 60 g of mixture of stabilised nanocurcumin prepared according to Example 2 i.e. 20 g of ground curcumin and 40 g of mannitol
  • 30 g of lecithin 30 g of lecithin
  • 0.2 g of piperine 0.2 g of piperine
  • 6.67 g of orange aroma All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 150 mg.
  • Example 4A To 1903 g of tablet substance prepared according to Example 4A, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of lecithin, 0.2 g of piperine and 6.67 g of peppermint aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B i.e. 20 g of ground curcumin and 40 g of mannitol
  • 30 g of lecithin 30 g of lecithin
  • 0.2 g of piperine 0.2 g of piperine
  • 6.67 g of peppermint aroma All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • Example 3 To 1633 g of tablet substance prepared according to Example 3, the substances as follows have been added: 24 g of mixture of stabilised nanocurcumin prepared according to Example 2, i.e. 8 g of ground curcumin a16 g of mannitol, 12 g of lecithin, 0,8 g of piperine and 6,67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • 24 g of mixture of stabilised nanocurcumin prepared according to Example 2 i.e. 8 g of ground curcumin a16 g of mannitol, 12 g of lecithin, 0,8 g of piperine and 6,67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • Example 4C To 1633 g of tablet substance prepared according to Example 4C, the substances as follows have been added: 24 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 8 g of ground curcumin and 16 g of mannitol, 12 g of lecithin, 0.8 g of piperine and 6.67 g of peppermint aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • Example 3 To 1423 g of tablet substance prepared according to Example 3, the substances as follows have been added: 45 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 15 g of ground curcumin and 30 g of mannitol, 12 g of lecithin, 0.8 g of piperine and 6.67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 300 mg.
  • Example 4B To 1423 g of tablet substance prepared according to Example 4B, the substances as follows have been added: 45 g of mixture of stabilised nanocurcumin prepared according to Example 2, i.e. 15 g of ground curcumin and 30 g of mannitol, 12 g of lecithin, 0.8 g of piperine and 6.67 g of peppermint aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 150 mg.
  • Example 3 To 1250 g of tablet substance prepared according to Example 3, the substances as follows have been added: 500 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 167 g of ground curcumin and 333 g of mannitol, 250 g of sunflower lecithin and 0.16 g of piperine. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • 500 g of mixture of stabilised nanocurcumin prepared according to Example 1B i.e. 167 g of ground curcumin and 333 g of mannitol
  • 250 g of sunflower lecithin 250 g of sunflower lecithin and 0.16 g of piperine. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 200 mg.
  • Example 4B To 1250 g of tablet substance prepared according to Example 4B, the substances as follows have been added: 500 g of mixture of stabilised nanocurcumin prepared according to Example 2, i.e. 167 g of ground curcumin and 333 g of mannitol, 250 g of sunflower lecithin and 0.16 g of piperine. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 300 mg.
  • Example 4A To 951,5 g of tablet substance prepared according to Example 4A, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of sunflower lecithin, 0.2 g of piperine and 6,67 g of orange aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 100 mg.
  • 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B i.e. 20 g of ground curcumin and 40 g of mannitol
  • 30 g of sunflower lecithin 30 g of sunflower lecithin
  • piperine 0.2 g of piperine
  • 6,67 g of orange aroma All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 100 mg.
  • Example 4A To 951,5 g of tablet substance prepared according to Example 4A, the substances as follows have been added: 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B, i.e. 20 g of ground curcumin and 40 g of mannitol, 30 g of sunflower lecithin, 0.2 g of piperine and 6,67 g of peppermint aroma. All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 100 mg.
  • 60 g of mixture of stabilised nanocurcumin prepared according to Example 1B i.e. 20 g of ground curcumin and 40 g of mannitol
  • 30 g of sunflower lecithin 30 g of sunflower lecithin
  • piperine 0.2 g of piperine
  • 6,67 g of peppermint aroma All these components have been homogenised and compacted using direct pressing and this way compact, porous tablets, have been produced, weighting 100 mg.
  • curcumin formulation Several types have been prepared:
  • Formulations of curcumin (4 mg) have been resuspended in 1 ml of PBS (buffer saline solution), sound treated in the bath for 5 minutes and 40 ⁇ l of this suspension has been added into 2 ml of a cultural medium to the cells (cell line U-2 OS, human osteosarcoma; cell line MCF-7, human breast carcinoma). Incubation with cells has run in an incubator at 37°C for 1 hour, and then reference dye Hoechst 33342 has been added in the medium for 15 minutes (resulting concentration 0.5 ⁇ M) which marks cell nuclei with fluorescence.
  • PBS buffer saline solution
  • the cells have been rinsed with the medium without phenol red, they have been viewed using a fluorescence inversion microscope Leica DM IRB using an oil immersion objective (x63) and scanned with a camera DFC 480.
  • the same cell field has been scanned using common light (phase contrast), and fluorescence cubes Leica A (excitation filter BP340-380 and long pass filter LP 425 for emission) showing blue fluorescence Hoechst 33342 and Leica I3 (excitation filter BP 450-490 and long-pass filter LP 515 for emission) showing green fluorescence of curcumin. All the tested variants of curcumin have been scanned with a camera with the same setting to allow their comparison. The snaps are presented in Figs. 5 and 6 . In vitro experiments have confirmed penetration of the prepared formulation into the cell system.
  • the method is based on quantification of fluorescence substance curcumin.
  • the methodology has been used to determine efficiency of intracellular transport of curcumin formulations where the results have been compared with native and micronized curcumin where we have observed very low intracellular absorption while some among the tested formulations have provided high values of intracellular fluorescence and these have been assessed quantitatively.
  • curcumin in cell can be quantified directly or in cell lysates without necessary pre-cleaning of a sample.
  • the assessment of fluorescence intensity has been performed using image analysis and software processing of the image of cells from a microscope where the ration of relative intensity of green fluorescence in the samples has been measured.
  • curcumin prepared according to Example 1B has been selected as the optimum bioavailable one.
  • curcumin according to this invention 220x better solubility against commercial native form of curcumin has been achieved.
  • Tablet 1 prepared according to Example 6 (2 mg of curcumin) and other 2 commercial preparations (2 mg of curcumin) have been resuspended in 1 ml PBS (buffer saline solution), sound treated in a bath for 5 minutes and 40 ⁇ l of this suspension has been added to 2 ml of a cultural medium to the cells of human osteosarcoma. Incubation with cells has run in an incubator at 37°C for 1 hour and then reference dye Hoechst 33342 has been added in the medium for 15 minutes (resulting concentration 0.5 ⁇ M) which marks cell nuclei with fluorescence.
  • PBS buffer saline solution
  • the cells have been rinsed with the medium without phenol red, they have been viewed using a fluorescence inversion microscope Leica DM IRB using an oil immersion objective (x63) and scanned with a DFC 480 camera.
  • the same cell field has been scanned using common light (phase contrast), and fluorescence cubes Leica A (excitation filter BP340-380 and long pass filter LP 425 for emission) showing blue fluorescence Hoechst 33342 and Leica I3 (excitation filter BP 450-490 and long pass filter LP 515 for emission) showing green fluorescence of curcumin. All the variants of curcumin tested have been scanned with a camera with the same setting to allow their comparison. In vitro experiments have confirmed penetration of the produced nanoformulation with ODT into a cell system much higher than for native curcumin in commercial preparations ( Fig. 6 ).
  • curcumin according to this invention For formulation of curcumin according to this invention, the real bioavailability has been achieved and this has been derived from comparison of fluorescence intensity of biologically available curcumin according to the invention against commercial native forms of curcumin products A and B.
  • Tablet 1 prepared according to Example 6 (2 mg of curcumin), native curcumin (2 mg), native curcumin micronized with mannitol according to Example 2 (2 mg of curcumin) and native curcumin micronized with mannitol, lecithin and piperine (2 mg of curcumin, 4 mg of mannitol, 3 mg of lecithin, 0.02 mg of piperine) have been resuspended in 1 ml of PBS (buffer saline solution ), sound treated in a bath for 5 minutes and 40 ⁇ l of this suspension has been added to 2 ml of a cultural medium to the cells of human osteosarcoma.
  • PBS buffer saline solution
  • curcumin according to this invention For formulation of curcumin according to this invention, the real bioavailability has been achieved and this has been derived from comparison of fluorescence intensity of biologically available curcumin according to the invention against native curcumin, native curcumin micronized with mannitol and native curcumin micronized with manitol, lecithin and piperine.

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Claims (14)

  1. Eine orodispersible Tablette mit biologisch verfügbarem Curcumin, die die biologische Verfügbarkeit einer Mischung aus stabilisiertem, biologisch verfügbarem Curcumin um 30 % erhöht, dadurch gekennzeichnet , dass sie einen orodispersiblen Träger und eine Formulierung von biologisch verfügbarem Curcumin enthält, wobei die Formulierung eine Mischung aus stabilisiertem, biologisch verfügbarem Curcumin in Lipid im Gewichtsverhältnis 0,35 bis 1,5:1 von Lipid zu Curcumin mit Anwesenheit von Piperin im Gewichtsverhältnis 0,0025 bis 0,1:1 von Piperin zu Curcumin enthält, wobei die Mischung Teilchen des Extrakts des Rhizoms der Pflanze Curcuma longa enthält, die mindestens 95 Gew.-% Curcumin enthalten, das auf trockene Weise in Mischung mit Mannitol im Gewichtsverhältnis 1 : 1 bis 3 gemahlen wurde und eine Teilchengröße von 100 - 250 nm hat, und der orodispersible Träger 20 bis 80 Gew.-% Tapiokastärke, 10 bis 30 Gew.-% pulverisierte Bambusfaser und 1 bis 20 Gew.-% säurehydrolysiertes Dextrin enthält.
  2. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass das Gewichtsverhältnis von Curcumin zu Mannitol 1:2 beträgt.
  3. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass die Teilchengröße des Curcumin-Extrakts 110 bis 180 nm beträgt.
  4. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass die Partikel des Curcumin-Extrakts durch Trockenstrahlmahlung oder Stiftmahlung gemahlen werden.
  5. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass das Lipid Lecithin ist.
  6. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass der orodispersible Träger 0,05 bis 10 Gew.-% Stevio-Rebauosid A enthält.
  7. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass der orodispersible Träger 1 bis 10 Gew.-% Isomalt enthält.
  8. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass sie bis zu 97 Gew.-% eines orodispersiblen Trägers enthält.
  9. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass der orodispersible Träger 10 bis 50 Gew.-% Erythrit oder Sorbit oder Xylit oder deren Gemisch enthält.
  10. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass der orodispersible Träger 1 bis 8 Gew.-% an Gleitmitteln enthält.
  11. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 10, dadurch gekennzeichnet, dass die Gleitmittel 0,5 bis 4 Gew.-% Siliciumdioxid und 0,4 bis 4 Gew.-% Glycerindibehenat und 0,01 bis 10 Gew.-% vorgelatinierte Stärke sind.
  12. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 10, dadurch gekennzeichnet, dass die Gleitmittel Magnesiumstearat, Aluminiumstearat, Natriumlaurylsulfat, Talkum, Polyethylenglykol, Stearinsäure, Borsäure oder deren Gemisch sind.
  13. Orodispersible Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1, dadurch gekennzeichnet, dass der orodispersible Träger 0,01 bis 10 Gew.-% Aroma oder Geschmack enthält.
  14. Verwendung der orodispersiblen Tablette mit biologisch verfügbarem Curcumin nach Anspruch 1 als Lebensmittelzusatzstoff.
EP18170818.1A 2017-05-08 2018-05-04 Mischung von stabilisiertem biologisch verfügbarem curcumin für orodispergierbare formulierungen, formulierungen von biologisch verfügbarem curcumin und orodispergierbare tablette mit biologisch verfügbarem curcumin und verwendung davon Active EP3400932B1 (de)

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